P773: CYCLOPHOSPHAMIDE COMBINED WITH PREDNISONE FOR CYCLOSPORINE-REFRACTORY/RELAPSED T-LARGE GRANULAR LYMPHOCYTE LEUKEMIA ASSOCIATED PURE RED CELL APLASIA
Authors: Xiaoqing Liu, Yue LI, Yuemin Gong, Yawen Zhang, Xinyu Zhang, Qiqiang Long, Guangsheng He, Jianyong LI
Journal: HemaSphere (2023)

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: T-large granular lymphocyte leukemia (T-LGLL) is a common cause of secondary pure red cell aplasia (PRCA). Considering the cytotoxicities of cyclophosphamide (CTX) and methotrexate (MTX), cyclosporine (CsA) is proposed as first-line treatment. Due to the rarity of this disease, few studies of subsequent therapy for patients failed to CsA have been reported. Aims: In order to propose therapeutic algorithms that may be helpful in guiding the management of CsA-refractory/relapsed T-LGLL associated PRCA patients. Methods: From January 2016 to December 2022, 65 patients with T-LGLL associated PRCA were enrolled. CsA was administered at a dose of 3–5mg/kg/day with a minimum concentration of 150–200ng/ml. CP regimen consisted of CTX and prednisone. CTX was initiated at a daily dose of 100mg, maintained to response. CTX was discontinued when lymphocyte percentage was lower than 50% of normal level or granulocyte count was less than 0.5×109/L. Prednisone was initiated at a dose of 0.5–1mg/kg/day and gradually typered to discontinuation after four weeks. Results: The median age at presentation was 60 (22–89) years, with 34 cases (52%) over 60 years old. Of the 65 patient cohort treated with CsA, 28 (43%) achieved response. The median time to optimum effect was 3 (1–11) months. The cumulative effect curve showed that 89% of all remission occurred within 9 months (Figure 1). 37 patients did not respond to CsA during a median duration time of 6(1–18) months. 24 patients refractory or resistant to CsA had switched to CP regimen. This yielded an overall response rate (ORR) of 79% (19/24) and complete response rate (CRR) of 63% (15/24). ORR (79% vs 43%, P=0.002) and CRR (63% vs 23%, P<0.001) were higher in CP regimen than in CsA. 90% of all response obtained within 3 months based on the cumulative effect curve of CP regimen (Figure 1). The median time to best response was 2 (0.5–7) months in CP group, which was shorter than in CsA (P=0.001). Out of 60 patients, STAT3 and STAT5b mutations were found in 13 (22%) and 1 (2%), respectively. Only one had more than one mutation. The most frequent mutation was Y640F, found in 7 cases (54%). Patients with STAT3/5b mutation were younger than those with STAT3/5b wild type (48 vs 61 years old, P=0.002). ORR for STAT3/5b mutated versus wild-type with CsA and CP were 6/14(43%) versus 21/46(46%) (P=0.854), 8/9(89%) versus 11/15(73%) (P=0.615), respectively. Response to CP was better than CsA in STAT3/5b- mutated patients (89% vs 43%, P=0.04). T-cell receptor (TCR) repertoire deep sequencing was conducted in 42 patients, 33of them showed predominant leukemic clones. 33% of the T-LGLL clones express the TRBV06 gene. The ORR of CsA in patients with TRBV06 gene expression (2/11) was markedly lower than in them without it (18/32) (18% vs 56%, P=0.029). CP regimen was equally effective in both positive (4/6) and negative (13/14) TRBV06-expressived cases (67% vs 93%, P=0.201). It seemed that CP responded better than CsA in patients showed TRBV06 gene (67% vs 18%, P=0.109), and more cases need to be added to confirm this difference. Binary-Logistic regression model was conducted in cases received CsA and CP therapy. In univariate and multivariate analysis, both leukemic clones belonged to TRBV06 family (P=0.023; P=0.013) and treated by CsA (P=0.004; P=0.005) had worse response (Table 1). Summary/Conclusion: Our results indicated that CP regimen was effective for patients who failed to CsA. The response rate of CsA in patients with STAT3/5b mutation or not was similar. Leukemic clones with TRBV06 gene were frequently detected in T-LGLL associated PRCA, which may related to CsA-refractory or resistant cases. The identification of TRBV06 gene may be useful for appropriately managing patients with T-LGLL associated PRCA.Keywords: Large granular lymphocytic leukaemia, Immune therapy, T cell repertoire, Pure red cell aplasia